Aminobenzoic acid derivatives

ABSTRACT

Compounds having the formula:   WHEREIN X is halogen and the non-toxic, pharmaceuticallyacceptable inorganic and organic salts thereof. Antiinflammatory compositions consisting essentially of at least one of said compounds in admixture with a non-toxic, pharmaceutically acceptable carrier. A method for reducing inflammation of the tissues in mammals comprising administering a therapeutically effective comcentration of at least one of said compounds, preferably in admixture with a non-toxic pharmaceutically acceptable carrier.

United States Patent 1 Borne Y AMINOBENZOIC ACID DERIVATIVES [7 5] Inventor: Ronald F. Borne, Oxford, Miss.

[73] Assignee: The University of Mississippi,

University, Miss.

[22] Filed: Nov. 7 1972 [21] Appl. No.2 304,485

[52] US. Cl. 260/518 A, 260/50l.1l, 424/319 [51] Int. Cl. C07c 143/80 [58] Field of Search 260/501.1l, 518 A [56] References Cited UNITED STATES PATENTS 3,682,968 8/1972 Shen et a1. 260/518 A Primary Examiner Lorraine A. Weinberger Assistant Examiner-4.. Arnold Thaxton Att0rneyWilliam D. Stokes [111 3,773,712 [451 Nov. 20, 1973 [57] ABSTRACT Compounds having the formula:

HOOOQ-NHSOGX wherein X is halogen and the non-toxic, pharmaceutically-acceptable inorganic and organic salts thereof. Antiinflammatory compositions consisting essentially of at least one of said compounds in admixture with a non-toxic, pharrnaceutically acceptable carrier. A method for reducing inflammation of the tissues in mammals comprising administering a therapeutically effective comcentration of at least one of said compounds, preferably in admixture with a nontoxic pharmaceutically acceptable carrier.

12 Claims, No Drawings 1 AMINOBENZOIC ACID DERIVATIVES BACKGROUND OF THE INVENTION For a considerable period of time there has been continuing interest in the discovery and development of more effective, non-steroidal, antiinflammatory agents which can be administered to mammals in therapeutically effective dosages with minimal side effects. There is also an economic need for such agents which are relatively simple to produce from readily available, noncostly reagents.

A wide variety of compounds have demonstrated antiinflammatory properties, as for example pyrazolidinediones, arylalkanoic acids, carboxylic acid amides, and salicylates. Anthranilic acid and certain of its derivatives, such as mefenamic acid, flufenamic acid, and N-benzoyl-anthranilic acid, have also exhibited antiinflammatory activity as described, for example in the article by M. W. Whitehouse, Biochemical Properties of Anti-Inflammatory Drugs, Biochem. Pharmacol., 16, pp. 753-760 (1967). The article also discloses that N- toluene-sulfonyl-anthranilic is virtually inactive as an antiinflammatory agent and postulates that this inactivity may be caused by steric hindrance of the carboxyl group by the sulfono group. However none of the known art has taught or suggested the monohalogenated N-benzene sulfonyl derivatives of aminobenzoic acid, their antiinflammatory properties, or their low degree of toxicity. In light of the prior art disclosing the inactivity of a known N-sulfono derivative, the activity of the halogenated derivatives of the invention is indeed surprising.

SUMMARY OF THE INVENTION The invention comprises new compounds having the formula:

no 0 0Q-wmm-Qx DESCRIPTION OF PREFERRED EMBODIMENTS The compounds are prepared as, for example, by reacting the mono-halogen substituted benzenesulfonyl chloride with aminobenzoic acid in dilute aqueous sodium hydroxide, acidifying the product, and then separating the resulting solid. Optimum yields are generally obtained when the pH of the basic solution of aminobenzoic acid is maintained between about 9.5 and 10.5 during addition of the substituted benzenesulfonyl chloride.

The salts can be formed by conventional techniques by reaction of the acid form of the compounds with a therapeutically acceptable inorganic base, such as sodium, potassium, or ammonium hydroxide, or an organic base, such as an amine, e.g., methylamine, dimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethanobdiethylamine, or the like. Such salts are often preferred because of their greater solubility.

The compounds of the invention have been found to be effective as antiinflammatory agents in mammals and can be used to reduce inflammation and relieve pain in diseases such as arthritis. They can also be used to control and reduce edema.

Treatment is preferably by oral administration of the compound in a pharmaceutically-acceptable carrier, which may be'solid or liquid. Examples of acceptable solid carriers include, but are not limited to, starch, dextrose, sucrose, lactose, gelatin, agar, stearic acid, magnesium stearate, acacia and the like. Examples of liquids include, but are not limited to, water, edible oils, such as corn or peanut oil, and the like.

When administered in solid form, the compound and diluent carrier may be in the form of tablets, capsules, powders, or lozenges prepared by standard techniques. When given as a liquid preparation, the mixture of active compound and liquid diluent carrier may be in the form of a liquid suspension administered as such or encapsulated.

The compounds have been found to be more effective as antiinflammatory agents than the standard phenylbutazone.

I When employed to treat an inflammatory condition ina mammal, animal or human, the active compound is preferably administered orally in admixture with a pharmaceutically acceptable diluent carrier as described above. The compound is administered in a nontoxic dosage concentration sufficient to reduce the inflammation or the edema where present. The actual dosage administered will be determined by such generally recognized factors as the body weight of the patient, the severity of the condition being treated, the idiosyncrasies of the particular patient, and the activity of the specific compound employed. With these considerations in mind, the daily dosage for a particular patient can be readily determined by the medical practitioner in accordance with conventional techniques in the medicinal art.

EXAMPLE 1 A solution of 0.06 mole (15.3g) of pbromobenzenesulfonyl chloride in 20 ml of dioxane was added to a solution of 0.05 mole (6.9g) of anthranilic acid dissolved in 2N NaOH at such a rate as to maintain the pH between 9.5 and 10.5. After addition, the resulting solution was stirred until no further pH decrease was observed. The solution was then acidified with cone. Hcl to a pH of between 2 and 3 and vigorously stirred. The resulting solid was collected, dried, and recrystallized from ETOH-l-I O to give an 82% yield of N-p bromobenzenesulfonyl-o-aminobenzoic acid, m.p. 221-223C. Analysis: calc. C 43.84%, H 2.84%, N 3.93%; actual C 43.83%, H 2.78%, N 3.79%.

EXAMPLE 2 The following compounds were prepared in accordance with the procedure described in Example 1:

N-p-fluorobenzenesulfonyI-o-amino-benzoic acid:

Analysis: calc.% C 52.89, H 3.42, N4.74

actual C 52.87, H 3.19, N 4.45 N-p-chlorobenzenesulfonyl-o-aminobenzoic acid:

m.p. l-203C Analysis: calc.% C 50.09, H 3.24, N 4.49

actual C 50.16, H 3,17, N 4.19

bromobenzenesulfonyl-o-amino-benzoic acid derivative showed more than twice the potency of phenylbutazone in the in vivo assays. This compound and the fluoro derivative also exhibited lower toxicity than n=No. oi determinations per cone. or dose level. b .T. Ben-Bassat. E. Peretz and F. G. Sulman, Arch. Int. Phamacodyn. Then, 122, 434

The antiinflammation activity of the compounds prepared in Examples 1 and 2 were tested by two techniques, one an experimental in vitro technique described by J. H. Brown et al Proc. Soc. Exptl. Biol. Med., 125, 837 (i967) and by the standard in vivo rat paw edema technique described by C. A. Winter et al J. Pharmacol. Exp Ther., 141, 369 (1963).

The in vitro technique has been employed to screen antiini'lammatory compounds by determining their ability toinhibit heat-induced hemolysis of red blood cells. The procedure, as described by J. H. Brown et al, supra, was followed except that fresh human blood from fasted Type 0+ donors was used rather than blood from anesthetized mongrel dogs. Fresh human blood has found to give more consistent results, possibly due to a lack of stabilizing action of the anesthetic.

The compounds were tested at three dose levels and compared to the standard phenylbutazone. Each value is the average of 6 separate values determined as triplicates on the blood of 3 to 5 separate subjects. The results are summarized in Table I.

Antiinflammatory activity was measured as inhibition of carrageenin-induced edema in the hind paw of the rat (Sprague Dawley, 150-200 g) according to the procedure of Winter et al, supra. Edema formation was measured 3 hours after an intra-peritoneal injection of test drug suspended in saline and Tween 60 and 2.5 hours after carrageenin injection. The edema inhibition of each compound (8 rats per group) was compared with animals receiving only the vehicle and animals receiving phenylbutazone. Each value is the average inhibition of paw edema measured in 16 to 24 rats. The results are summarized in Table l.

The LD of the compounds was determined by the method of J. T. Litchfield et al. J. Pharrnacol. Exp. Ther., 96, 99 (1949) using four dose levels for each compound. Results are summarized in Table II.

It will be noted that the compounds of the invention were more effective than phenylbutazone in both the in vitro and in vivo assays. The N-p- Although this invention has been described with reference to illustrative embodiments thereof, it will be apparent to those skilled in the art that the principles of this invention can be embodied in other forms but within the scope of the claims.

I claim:

1. Compounds having the formula:

7. The compounds of claim 3 wherein the halogen is in para position. 

2. The compounds of claim 1 wherein the halogen is F, Cl, or Br.
 3. The compounds of claim 1 wherein the -COOH group is in ortho position.
 4. The compounds of claim 2 wherein the -COOH group is in ortho position.
 5. The compounds of claim 1 wherein the halogen is in para position.
 6. The compounds of claim 2 wherein the halogen is in para position.
 7. The compounds of claim 3 wherein the halogen is in para position.
 8. The compounds of claim 4 wherein the halogen is in para position.
 9. The compounds of claim 2 wherein the halogen is bromine.
 10. The compounds of claim 4 wherein the halogen is bromine.
 11. The compounds of claim 6 wherein the halogen is bromine.
 12. The compound N-p-bromobenzenesulfonyl-o-amino benzoic acid and the non-toxic pharmaceutically acceptable inorganic or organic salts thereof. 